This is a proposal to establish an Autoimmunity Center of Excellence (ACE) in Philadelphia. Four leading institutions are joining forces to create an ACE, to study autoimmunity from bench to bedside. Investigators from Thomas Jefferson University, Temple University, University of Pennsylvania and Children's Hospital of Philadelphia will participate in various aspects of this ACE. These institutions combine strong scientific bases in immunology with longstanding excellence in the management of patients with various autoimmune disorders, making Philadelphia an ideal place for establishing this Center. The Philadelphia ACE proposes 2 clinical trial concepts, 2 basic science projects and one pilot project. The clinical trial concepts are: 1) a phase I trial of a novel therapeutic antibody, which blocks LFA-1, in patients with scleroderma;and 2) a phase I trial of an oral, soy-derived, natural protease inhibitor, Bowman-Birk Inhibitor Concentrate, in multiple sclerosis. The research component consists of 3 projects: 1) investigation of the recently discovered Th17 cells in humans and their regulation in multiple sclerosis, 2) translation of recent findings on the importance of the mer family of tyrosine kinases in murine autoimmunity to systemic lupus erythematosus;and 3) a pilot project to develop a hematopoietically humanized NOG mouse model. This model will be an invaluable tool to study human autoimmune diseases. The Center has 2 cores: A) flow cytometry/cell sorting core, to centralize the FACS analyses required in the projects;and B) administrative core, for administration of the Center and facilitating interaction between clinicians and basic scientists involved in the different projects. Autoimmune diseases have considerable negative impact on public health. The proposed ACE will investigate fundamental mechanisms of autoimmunity. Further, the ACE proposes to conduct trials of two therapeutic agents for treatment of patients with autoimmune diseases. Thus, the proposed ACE will be a valuable and relevant asset in the pursuit of improved public health. CLINICAL COMPONENT (Jimenez, S) CLINICAL COMPONENT DESCRIPTION (provided by applicant): The clinical component of the Philadelphia ACE brings together clinician-investigators, physician-scientists and basic scientists from four Philadelphia institutions to perform clinical trials of new and promising agents for the treatment of various autoimmune disorders. Clinician-investigators with expertise and experience in clinical trials are proposing clinical trial concepts. Physician-scientists and basic scientists familiar with the diseases will collaborate with clinicians in endeavoring to understand the basic mechanisms of action of these new agents and, in the process, to better understand the disease itself. All four institutions are interested and willing to submit clinical trial concepts to the Steering Committee of the ACE. Initially, the Center will focus on the following two clinical trial concepts: 1) Phase I trial of a novel therapeutic agent, which blocks LFA-1, in patients with scleroderma;2) Phase I trial of an oral, soy-derived natural protease inhibitor, Bowman-Birk Inhibitor Concentrate, in multiple sclerosis. The participating institutions have outstanding infrastructure and the expertise to perform first-class clinical trials. Details on institutional resources, on clinics specialized in several autoimmune disorders and the potential to recruit patients for other ACEs are given in this section. The Clinical Component proposes novel clinical trial concepts and studies to understand the mechanisms of action of the therapeutics being tested. As such, they are an integral part of this ACE.